Muscle protein wasting occurs in HIV-infected individuals and is often the initial indication of AIDS. The alterations in muscle protein metabolism that explain AIDS-wasting are unknown. Seven subjects with AIDS-wasting (CD4<200/mm3, HIV mRNA= 7.1x105 copies/ml) chronic stable opportunistic infections (OI) and >10% weight loss, 10 HIV-infected men and 1 woman (CD4>200/mm3, HIV mRNA= 3.3x103 copies/ml) without wasting or OI (asymptomatic), and 6 HIV-negative lean men (control) were studied. Constant intravenous infusions of 1-[13C]-leucine and 2-[15N]-glutamine were used to assess plasma leucine and glutamine rate of appearance (Ra), whole-body leucine oxidation rate, and 13C-leucine incorporation rate into whole-body and mixed muscle protein. Fasting whole-body proteolysis and synthesis rates were increased (P<0.05) above control in the asymptomatic HIV-infected subjects, and further increased (P<0.05) in AIDS-wasting. Fasting mixed muscle protein synthesis rate was increased in the asymptomatic subjects (P<0.05), but similar in AIDS-wasting and control subjects. Plasma glutamine Ra was increased (P<0.001) in AIDS-wasting subjects, but similar in control and asymptomatic subjects. These findings suggest that AIDS-wasting results from; (a) a preferential reduction in muscle protein, (b) a failure to sustain an elevated rate of mixed muscle protein synthesis while whole-body protein turnover is increased, and (c) a significant increase in glutamine release into the circulation, probably from muscle proteolysis. The reason for the increased glutamine Ra in AIDS-wasting is unknown, but several interesting possibilities exist.